|
The medical journal 'Primary Psychiatry' published the following long letter from me in the April 1996 issue, in response to a case-report in the January issue.
Re: 'Case Report: The Psychiatric Manifestations
of B12 Deficiency', Jan., '96
Sir,
B12 deficiency is such an often-missed diagnosis, with such devastating consequences, that I am always grateful to authors of such papers when they do publish one [1].
It is indeed sad that the described patient had to go through so many psychiatrists, for 2.5 years, before the diagnosis was made, since the diagnostic delay may well be the reason for the equivocal response of her dementia to treatment; her diagnosis was made only after 2 years and in the 5th/ last stage of B12 deficiency, which is often neuropsychiatrically irreversible [2-4]. However, I believe there are 2 other possible explanations for her undramatic response to B12 treatment: 1 Suboptimal B12 dosing and frequency; and 2 Other possibly-reversible deficiency states that may also have played a role in her dementia, such as 'subclinical' hypothyroidism, folate, zinc and other mineral deficiencies, and copper toxicity.
The authors are not to be faulted as they followed the standard approach and treatment; but there are indications that these other conditions could have been present despite the thorough work-up the patient received, by current standards. As early as 1960, Smith already pointed out that the neuropsychiatric manifestations of B12 deficiency take higher doses and a longer period of treatment for reversal to occur [5]; and this view was reaffirmed in 1972 [6]. A recent report points to the greater assimilation of B12 from the 1000mcg injections than from the 100mcg ones, without any disadvantage in cost or toxicity [7]; and indeed Newbold proved that even 3000mcg IM t.i.d., producing serum B12 levels as high as 800,000 pg/ml on an indefinite basis, caused no toxicity and many psychiatric benefits [8]! I have gained a distinct sense that we physicians, neurologists and psychiatrists have been miserly with our B12 diagnoses and treatments. Many patients require 1000 mcg IM every 2 weeks (or 2,000-2,500 mcg by mouth twice-daily) as maintenance, in order to keep their serum B12 levels optimal (between 1,000 and 2,000 pg/ml, in the troughs).
As far as other possible causes of her dementia are concerned, 'subclinical' hypothyroidism is one, and the standard 'thyroid panel' would not necessarily pick this up, while the free-T4, free-T3 and 3rd-generation TSH levels would [9-11]. Folate deficiency is a now-well-known cause of reversible dementia [12-15]; this patient's serum folate could have been elevated by a single infusion of multivitamins in the ER prior to her admission to the geriatric psychiatry floor, whereas an RBC-folate level would have reflected the previous several months' folic acid status. Zinc deficiency, which was not tested, has also been seen as a cause of dementia [16-18]; and so has copper toxicity [19], commonly occurring as a result of the use of copper pipes for the plumbing in many American homes.
This patient's B12 deficiency was finally picked up, when first seen by the authors, when her level had dropped to an unmeasurably-low level (<40 pg/ml). Most US labs still give the 'normal' range as 200-1100 pg/ml, even though there are numerous papers, in prestigious mainstream journals, showing that when the serum level drops below 500 or 550 pg/ml the CSF level can become deficient [20-26], and of course that is the important level for the neuropsychiatric manifestations of the disease. And this is without considering an associated low folate or zinc level, or high copper level, to mitigate against even a normal B12 level. Neurologists and psychiatrists have allowed hematologists and pathologists to define for us what is a normal B12 level, despite all our evidence to the contrary. In Japan, these neurologically- and psychiatrically-oriented journal articles are obviously taken into account because the normal range for serum B12 there is 500-1300 pg/ml 23. This is probably a large part of the explanation why Japan has such a low rate of 'Alzheimer's dementia' - and the US has such a high rate. This woman's B12 level may have been measured in the 2.5 yrs prior to the diagnosis being made but, since it may have been >200, it could have been passed as 'normal'. Or the serum B12 level may have been only 113 pg/ml but, because the Schilling's Test was normal, she was regarded as non-deficient: This actually happened in a late-onset-mania case described in the Canadian Journal of Psychiatry in June of 1993, in which the diagnosis of B12 deficiency (as the obvious cause of this case of secondary mania) was not even considered! [27]
I appreciated the references to obsessive compulsive disorder being caused by B12 deficiency; since any organic brain damage can cause it, I had suspected it could be caused by B12 deficiency but had not seen any evidence in the literature. I did not appreciate the weight given to Hector and Burton [28]: Their paper is one of the reasons why B12 deficiency is still so lightly regarded as a cause of numerous neuropsychiatric conditions, including peripheral neuropathy.
- Zisselman MH, Kim E, Sharretts RE, et al. Case report: The
psychiatric manifestations of B12 deficiency. Primary Psychi
1996; 3, 1: 50-55.
- Dommisse JV. Subtle vitamin-B12 deficiency and psychiatry:
An often-unnoticed but devastating relationship? Med Hypoth
1991; 34: 131-140.
- Swain R. An update of vitamin B12 metabolism and deficiency
states. J Fam Pract 1995; 41, 6: 595-600.
- Cunha UG, Rocha FL, Peixoto JM, et al. Vitamin B12 deficiency
and dementia. Int Psychogeriatr 1995; 7, 1: 85-8.
- Smith ADM. Megaloblastic madness. Brit Med J 1960; 2: 1840.
- Whitehead JA, Chohan MM. Paraphrenia and pernicious anemia.
Geriatrics 1972; May: 148-158.
- Watts DT. Vitamin B12 replacement therapy: How much is enough?
Wis Med J 1994; 93, 5: 203-5.
- Newbold HL. Vitamin-B12: Placebo or neglected therapeutic
tool? Med Hypoth 1989; 28: 155-164.
- Braverman LE, Utiger RD, eds (and 114 contributors). WERNER
and INGBAR'S "The THYROID: A Fundamental and Clinical Text",
6th ed.. Philadelphia: JB Lippincott, 1991.
- Evered DC, Ormston BJ, Smith PA et al. Grades of hypothyroidism.
Brit Med J 1973; 1: 657.
- Dommisse JV. (Free-)T3 is at least as important as (Free-)T4
in all cases of hypothyroidism (ltr). J Clin Psychi 1993;
54, 7 (July): 277-8.
- Sapira JD, Tullis S and Mullaly R. Reversible dementia due
to folate-deficiency. Southern Med J 1975; 6: 776-777.
- Sneath P, Chanarin I, Hodkinson HM et al. Folate status
in a geriatric population and its relation to dementia. Age
& Ageing 1973; 2: 177-182.
- Strachan RW and Henderson JG. Dementia and folate-deficiency.
Quarterly J Med 1967; 34, 142 (April): 189-204.
- Melamed E, Reches A and Hershko C. Reversible CNS-dysfunction
in folate deficiency. J Neurological Sci 1975; 25: 93-98.
- Burnet FM. A possible role of zinc in the pathology of dementia.
Lancet 1981; 1, 8213: 186-8.
- Constantinidis J. Zinc deficiency may be a factor in the
development of neurofibrillary tangles in Alzheimer's disease.
Int Conf Alzh Dis and Related Dis, Toronto, 1990. Reported
by Clinical Psychiatry News, Oct., 1990.
- VanTiggelen CJM. Alzheimer's Disease and alcohol dementia:
Association with zinc deficiency and cerebral vitamin B12
deficiency. J Orthomolecular Psychi 1984; 13, 2: 97-104.
- Sandstead HH. A brief history of the influence of trace
elements on brain function. Am J Clin Nutr 1986; 43 (Feb):
293-298.
- VanTiggelen CJM, Peperkamp JPC and TerToolen JFW. Assessment
of vitamin-B12 status in CSF. Am J Psychi 1984; 141, 1 (Jan.):
136-137.
- Lindenbaum J, Healton EB, Savage DG et al.. Neuropsychiatric
disorders caused by cobalamin deficiency in the absence of
anemia or macrocytosis. N Eng J Med 1988; 318, 26: 1720-1728.
- Regland B. VITAMIN-B12 DEFICIENCY IN DEMENTIA DISORDERS
(monograph/ doctoral thesis, comprising 6 papers, with co-authors).
Dept of Psychi. and Neurochem., University of Goteborg, Sweden,
1991 (Jan.).
- Mitsuyama Y and Kogoh H. Serum and cerebrospinal fluid vitamin-B12
levels in demented patients with MH3-B12 treatment - Preliminary
study. Japan J Neurol & Psychi 1988; 42, 1: 65-71.
- Ikeda T, Furukawa Y, Mashimoto S, Takahashi K and Yamada
M. Vitamin-B12 levels in serum and cerebrospinal fluid of
people with Alzheimer's disease. Acta Scand Psychiatr 1990;
82, 4 (Oct.): 327-329.
- Nijst TQ, Wevers RA, Schoonderwaldt HC, Hommes OR and DeHaan
AF. Vitamin-B12 and folate concentrations in serum and cerebrospinal
fluid of neurological patients, with special reference to
multiple sclerosis and dementia. J Neurol Neurosurg & Psychi
1990; 53, 11 (Nov.): 951-954.
- Enk C, Hougaard K and Hippe. Reversible dementia and neuropathy
associated with folate deficiency 16 years after partial gastrectomy.
Scand J Hematol 1980; 25: 63-66.
- Gnam W, Flint AJ. New-onset rapid-cycling bipolar disorder
in an 87-year-old woman. Can J Psychi 1993; 38: 324-6.
- Hector M, Burton JR. What are the psychiatric manifestations
of vitamin-B12 deficiency? J Am Geriatr Soc 1988; 36, 12:
1105-1112.
Yours faithfully,
John V DOMmisse, MD, FRCPC
|